title: Characterization of opioid activities of endomorphin analogs with C-terminal amide to hydrazide conversion.
abstract: Previously, we have synthesized an endomorphin-2 (EM-2) analog with C-terminal amide to hydrazide conversion, exhibiting slightly lower μ-affinity than EM-2. In the present study, the influence of C-terminal amide group to hydrazide conversion on the in vitro and in vivo opioid activities of EMs was evaluated. Our results demonstrated that C-terminal amide to hydrazide conversion of EMs did not markedly change their μ-opioid receptor binding affinities. Nevertheless, EM-2-NHNH2 decreased guinea pig ileum (GPI) and mouse vas deferens (MVD) potencies by about 10- and 5-fold compared to the parent compound, respectively. It is noteworthy that EM-1-NHNH2 exhibited the highest antinociception after intracerebroventricular (i.c.v.) injection, about 1.5-fold more potent than EM-1, but with moderate colonic contractile and expulsive effects, comparable with EM-1. Additionally, though EM-2-NHNH2 showed a slightly lower antinociceptive effect than EM-2, at higher doses (i.c.v., 1.5 and 5 nmol/mouse) the inhibitory effects of colonic propulsion were significantly attenuated, which would be helpful in the development of suitable μ-opioid therapeutics, but without some undesirable side effects. Therefore, the present results gave the evidence that C-terminal amide to hydrazide conversion of EMs may play an important role in the regulation of opioid activities.
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China. Electronic address: wangcl@hit.edu.cn.
authors.forename: Chang-Lin
authors.initials: CL
authors.lastname: Wang
authors.forename: Yu-Kun
authors.initials: YK
authors.lastname: Ren
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xiang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.forename: Che
authors.initials: C
authors.lastname: Lu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000502:physiology; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; C000588955:EM-1-NHNH2; C000588956:EM-2-NHNH2; D009479:Neuropeptides; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2
keywords: Antinociception; C-terminal amide; Colonic contraction and propulsion; Endomorphins; μ-Opioid receptor